Identification of Potential Risk Genes and the Immune Landscape of Idiopathic Pulmonary Arterial Hypertension via Microarray Gene Expression Dataset Reanalysis

Gene dysfunction and immune cell infiltration play an essential role in the pathogenesis of idiopathic pulmonary arterial hypertension (IPAH). We aimed to investigate the immune landscape and novel differentially expressed genes (DEGs) of IPAH. In addition, potential druggable molecular targets for IPAH were also explored. In this study, the GSE117261 dataset was reanalyzed to explore the immune landscape and hub DEGs of IPAH. Lasso Cox regression analysis and receiver operating characteristic curve analysis were performed to detect the predictive value of IPAH. Additionally, the underlying drug targets for IPAH treatment were determined by drug–gene analysis. IPAH was significantly associated with the transforming growth factor-β (TGF-β) signaling pathway and Wnt signaling pathway as well as energetic metabolism dysfunction. We identified 31 upregulated and 39 downregulated DEGs in IPAH patients. Six hub genes, namely, SAA1, CCL5, CXCR1, CXCR2, CCR1, and ADORA3, were related to IPAH pathogenesis regardless of sex differences. Prediction model analysis showed that the area under the curve values of the hub DEGs except CXCR2 were all above 0.9 for distinguishing IPAH patients. In addition, the relative proportions of 5 subtypes of immune cells, namely, CD8+ T cells, CD4+ memory resting T cells, γ delta T cells, M1 macrophages, and resting mast cells, were significantly upregulated in the IPAH samples, while 6 subtypes of immune cells, namely, CD4+ naive T cells, resting NK cells, monocytes, M0 macrophages, activated mast cells, and neutrophils, were downregulated. Additionally, a total of 17 intersecting drugs targeting 5 genes, CCL5, CXCR1, CXCR2, CCR1, and ADORA3, were generated as potential druggable molecular targets for IPAH. Our study revealed the underlying correlations between genes and immune cells in IPAH and demonstrated for the first time that SAA1, CCL5, CXCR1, CCR1, and ADORA3 may be novel genetic targets for IPAH.

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Identification of Potential Biomarkers and Immune Infiltration Characteristics in Idiopathic Pulmonary Arterial Hypertension Using Bioinformatics Analysis

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.624714 ◽

2021 ◽

Vol 8 ◽

Author(s):

Haowei Zeng ◽

Xiaoqin Liu ◽

Yushun Zhang

Keyword(s):

T Cells ◽

Pulmonary Arterial Hypertension ◽

Mast Cells ◽

Immune Cells ◽

Validation Cohort ◽

Enrichment Analysis ◽

Idiopathic Pulmonary Arterial Hypertension ◽

Immune Infiltration ◽

Pulmonary Arterial ◽

Potential Biomarkers

Objectives: Idiopathic pulmonary arterial hypertension (IPAH) is a rare but severe lung disorder, which may lead to heart failure and early mortality. However, little is known about the etiology of IPAH. Thus, the present study aimed to establish the differentially expressed genes (DEGs) between IPAH and normal tissues, which may serve as potential prognostic markers in IPAH. Furthermore, we utilized a versatile computational method, CIBERSORT to identify immune cell infiltration characteristics in IPAH.Materials and Methods: The GSE117261 and GSE48149 datasets were obtained from the Gene Expression Omnibus database. The GSE117261 dataset was adopted to screen DEGs between IPAH and the control groups with the criterion of |log2 fold change| ≥ 1, adjusted P < 0.05, and to further explore their potential biological functions via Gene Ontology analysis, Kyoto Encyclopedia of Genes and Genomes Pathway analysis, and Gene Set Enrichment Analysis. Moreover, the support vector machine (SVM)-recursive feature elimination and the least absolute shrinkage and selection operator regression model were performed jointly to identify the best potential biomarkers. Then we built a regression model based on these selected variables. The GSE48149 dataset was used as a validation cohort to appraise the diagnostic efficacy of the SVM classifier by receiver operating characteristic (ROC) analysis. Finally, immune infiltration was explored by CIBERSORT in IPAH. We further analyzed the correlation between potential biomarkers and immune cells.Results: In total, 75 DEGs were identified; 40 were downregulated, and 35 genes were upregulated. Functional enrichment analysis found a significantly enrichment in heme binding, inflammation, chemokines, cytokine activity, and abnormal glycometabolism. HBB, RNASE2, S100A9, and IL1R2 were identified as the best potential biomarkers with an area under the ROC curve (AUC) of 1 (95%CI = 0.937–1.000, specificity = 100%, sensitivity = 100%) in the discovery cohort and 1(95%CI = 0.805–1.000, specificity = 100%, sensitivity = 100%) in the validation cohort. Moreover, immune infiltration analysis by CIBERSORT showed a higher level of CD8+ T cells, resting memory CD4+ T cells, gamma delta T cells, M1 macrophages, resting mast cells, as well as a lower level of naïve CD4+ T cells, monocytes, M0 macrophages, activated mast cells, and neutrophils in IPAH compared with the control group. In addition, HBB, RNASE2, S100A9, and IL1R2 were correlated with immune cells.Conclusion:HBB, RNASE2, S100A9, and IL1R2 were identified as potential biomarkers to discriminate IPAH from the control. There was an obvious difference in immune infiltration between patient with IPAH and normal groups.

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Understanding the Role of CD4+CD25high (So-Called Regulatory) T Cells in Idiopathic Pulmonary Arterial Hypertension

Respiration ◽

10.1159/000114655 ◽

2008 ◽

Vol 75 (3) ◽

pp. 253-256 ◽

Cited By ~ 8

Author(s):

Frédéric Perros ◽

Sylvia Cohen-Kaminsky ◽

Marc Humbert

Keyword(s):

T Cells ◽

Pulmonary Arterial Hypertension ◽

Regulatory T Cells ◽

Arterial Hypertension ◽

Idiopathic Pulmonary Arterial Hypertension ◽

Pulmonary Arterial

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Alterations in circulating helper T-cells in idiopathic pulmonary arterial hypertension

10.1183/13993003.congress-2019.pa5051 ◽

2019 ◽

Author(s):

Denise van Uden ◽

Menno Van Nimwegen ◽

Thomas Koudstaal ◽

Peter Heukels ◽

Jennifer Van Hulst ◽

...

Keyword(s):

T Cells ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Idiopathic Pulmonary Arterial Hypertension ◽

Helper T Cells ◽

Pulmonary Arterial

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Overexpression of PD-1 on Peripheral Blood Lymphocytes in Patients with Idiopathic Pulmonary Arterial Hypertension and Its Association with High Viral Loads of Epstein-Barr Virus and Poor Clinical Parameters

Journal of Clinical Medicine ◽

10.3390/jcm9061966 ◽

2020 ◽

Vol 9 (6) ◽

pp. 1966 ◽

Cited By ~ 1

Author(s):

Michał Tomaszewski ◽

Ewelina Grywalska ◽

Andrzej Tomaszewski ◽

Piotr Błaszczak ◽

Marcin Kurzyna ◽

...

Keyword(s):

T Cells ◽

Immune System ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Epstein Barr Virus ◽

Idiopathic Pulmonary Arterial Hypertension ◽

Barr Virus ◽

Ebv Infection ◽

Pulmonary Arterial ◽

Epstein Barr

Idiopathic pulmonary arterial hypertension (IPAH) is a rare but severe disease with the elevated blood pressure in the pulmonary arteries without a known trigger of vascular remodelling. It leads to the right heart failure with reduced survival. Changes in the immunological landscape of the lungs and the periphery are common in IPAH patients, suggesting an immune system dysfunction. A cohort of 25 IPAH patients was enrolled in our study to investigate a link between the patient’s clinical status, immune parameters of the blood, and the Epstein–Barr virus (EBV) infection. We found significant alterations of the patients’ peripheral blood parameters. Therein, T lymphocytes and NK cell counts were decreased in the IPAH patients’ blood, while the proportion of regulatory T cells was increased. Additionally, levels of proinflammatory cytokines interleukin-6 (IL-6), IL-2, and interferon-gamma (IFN-γ) were elevated. We identified a weak correlation between EBV loads and IPAH patients’ clinical state (r = 0.54) and between EBV loads and overexpression of PD-1 on helper T cells (r = 0.56). We speculate that a significant dysregulation of the immune system homeostasis observed in IPAH patients may contribute to increased susceptibility of those patients to EBV infection, yet further longitudinal studies are required to characterize this relation in detail.

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Comprehensive identification of signaling pathways for idiopathic pulmonary arterial hypertension

AJP Cell Physiology ◽

10.1152/ajpcell.00382.2019 ◽

2020 ◽

Vol 318 (5) ◽

pp. C913-C930

Author(s):

Bingxun Liu ◽

Liping Zhu ◽

Ping Yuan ◽

Glenn Marsboom ◽

Zhigang Hong ◽

...

Keyword(s):

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Intracellular Calcium ◽

Signaling Pathways ◽

Signaling Pathway ◽

Cell Function ◽

Idiopathic Pulmonary Arterial Hypertension ◽

Channel Blockers ◽

Gpcr Signaling ◽

Pulmonary Arterial

Whole exome sequencing (WES) was used in the research of familial pulmonary arterial hypertension (FPAH). CAV1 and KCNK3 were found as two novel candidate genes of FPAH. However, few pathogenic genes were identified in idiopathic pulmonary arterial hypertension (IPAH). We conducted WES in 20 unrelated IPAH patients who did not carry the known PAH-pathogenic variants among BMPR2, CAV1, KCNK3, SMAD9, ALK1, and ENG. We found a total of 4,950 variants in 3,534 genes, including 4,444 single-nucleotide polymorphisms and 506 insertions/deletions (InDels). Through the comprehensive and multilevel analysis, we disclosed several novel signaling cascades significantly connected to IPAH, including variants related to cadherin signaling pathway, dilated cardiomyopathy, glucose metabolism, immune response, mucin-type O-glycosylation, phospholipase C (PLC)-activating G protein-coupled receptor (GPCR) signaling pathway, vascular contraction and generation, and voltage-dependent Ca2+ channels. We also conducted validation studies in five mutant genes related to PLC-activating GPCR signaling pathway potentially involved in intracellular calcium regulation through Sanger sequencing for mutation accuracy, qRT-PCR for mRNA stability, immunofluorescence for subcellular localization, Western blotting for protein level, Fura-2 imaging for intracellular calcium, and proliferation analysis for cell function. The validation experiments showed that those variants in CCR5 and C3AR1 significantly increased the rise of intracellular calcium and the variant in CCR5 profoundly enhanced proliferative capacity of human pulmonary artery smooth muscle cells. Thus, our study suggests that multiple genetically affected signaling pathways take effect together to cause the formation of IPAH and the development of right heart failure and may further provide new therapy targets or putative clues for the present treatments such as limited therapeutic effectiveness of Ca2+ channel blockers.

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